ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3796G>A (p.Gly1266Arg) (rs121907992)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000004053 SCV000192351 pathogenic Wilson disease 2013-12-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000004053 SCV000694454 pathogenic Wilson disease 2017-04-20 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.3796G>A (p.Gly1266Arg) variant involves the alteration of a highly conserved nucleotide. The variant is located within the putative ATP binding site of the conserved P-type ATPase Cu-like domain and 5/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by the functional study, Huster_2012, where G1266R was shown to markedly affect copper transport and abolish catalytic phosphorylation. This variant was found in 6/120738 control chromosomes at a frequency of 0.000049, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant was identified in multiple affected individuals in compound heterozygosity with clinically and biochemically confirmed Wilsons disease (WD). The codon Gly1266 appears to be a mutational hot-spot, as other alteration, such as p.G1266E, p.G1266W and p.G1266V, have been reported in patients with WD. Taken together, this variant is classified as Pathogenic.
Counsyl RCV000004053 SCV000790258 pathogenic Wilson disease 2017-03-23 criteria provided, single submitter clinical testing
Invitae RCV000004053 SCV001205969 pathogenic Wilson disease 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1266 of the ATP7B protein (p.Gly1266Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121907992, ExAC 0.01%). This variant has been observed in individual(s) with Wilson disease (PMID: 7626145, 21610751, 11243728). ClinVar contains an entry for this variant (Variation ID: 3849). This variant has been reported to affect ATP7B protein function (PMID: 22240481, 22692182). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004053 SCV000024219 pathogenic Wilson disease 1995-02-01 no assertion criteria provided literature only

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